Trilocked Photodynamic Senolytic Inducer Potentiating Immunogenic Senescent Cell Removal for Liver Fibrosis Resolution

Abstract

Liver fibrosis is a major global health problem without effective therapies, and targeted elimination of senescent cells is beneficial for hepatic function and organism survival. We report a new trilocked photodynamic senolytic inducer (PDSI) strategy for liver fibrosis resolution using a type-I photodynamic agent for immunogenic clearance of senescent cells. We demonstrate that this trilocked PDSI not only facilitates efficient production of superoxide anions (O₂^•–) in lysosomes of senescent cells for photodynamic therapy, but also permits NIR fluorescence and photoacoustic (NIRF/PA) imaging of senescent cells. Mechanistic investigation reveals that the trilocked PDSI elicited senescent cell clearance predominantly via the immunogenic necroptosis pathway. Moreover, this PDSI with a liver-targeting moiety enables high-contrast NIRF/PA imaging and effective liver fibrosis resolution in vivo. This liver-targeting PDSI exhibits remarkable immunogenic ablation of senescent cells, with enhancing dendritic cell maturation and cytotoxic T cell recruitment in liver fibrosis. Our study highlights the potential of trilocked type I PDSI for boosting immunity for senescent cell clearance and liver fibrosis treatment.